Proliferation of cholangiocytes is critical for the maintenance of biliary mass and secretory function during the pathogenesis of chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases (i.e., cholangiopathies) target cholangiocytes of varying size and have a heterogeneous, spotty pathology. Although sensory innervation is present in the liver as dense neural networks in the fibromuscular layer of the biliary tree, little information exists regarding its role in the regulation of biliary proliferation and function in normal and diseased states. We have obtained novel preliminary data indicating that sensory neuropeptides, released by sensory neurons innervating the biliary tree differentially, regulate the proliferation of small [via substance P (SP)] and large [via calcitonin gene related peptide (CGRP) and SP] cholangiocytes, thus suggesting that the sensory nervous system plays a potential key role in the heterogeneous proliferative responses of cholangiocytes to cholestasis and liver injury. The overall objective of this application is to determine the role that sensory innervation and sensory neuropeptides play in the maintenance of biliary mass during cholestasis and hepatoxin-induced liver damage. Based upon strong preliminary findings, we propose the novel central hypothesis that small and large cholangiocyte proliferation is regulated by sensory neuropeptides during the development of cholestasis and liver injury. Our proposed work will focus on three specific aims that have been designed to test the following working hypotheses: (i) that SP- positive sensory innervation plays a unique regulatory role in the modulation of small cholangiocyte proliferation;(ii) CGRP and SP-positive sensory innervation play a key regulatory role in large cholangiocyte proliferation;and (iii) sensory innervation and neuropeptides play a key regulatory role for controlling the differential proliferation of small and large cholangiocytes during in vivo models of liver disease. Hence, the elucidation of the intracellular mechanisms controlling the differential proliferative responses of small and large cholangiocytes to cholestasis and injury and its regulation by the sensory innervation of the liver will play a paramount role in the development of therapeutic strategies for the treatment of cholestatic liver diseases, which represent a major public health concern leading to liver transplantation or mortality. PUBLIC HEALTH RELEVANCE: The health relatedness of this application is that effective treatments are lacking for chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases cause damage to the bile ducts of the liver. The rationale for our research is that the successful completion of the studies can ultimately be expected to provide a greater understanding of cholestatic liver disease progression and increase opportunities for the development of novel treatment paradigms for chronic liver diseases.